It is well known that liver is an organ having an extremely high ability of regenerating itself. However, in a case of chronic hepatic disease, liver undergoes fibrosis during the process of the liver regeneration after continuous necrosis of hepatocytes, resulting in suppressing normal hepatocyte regeneration. This may be assumed to be due to a reduced sinusoidal blood flow resulting from an increase in an extracellular matrix involved in hepatic fibrosis, and also due to loss of space for the liver regeneration resulting from the occupation by the fibers produced.
The production of an extracellular matrix involved in hepatic fibrosis takes place mainly in an activated HSC (hepatic stellate cell). When the HSC is activated by cytokines such as TGF (transforming growth factor)-β or PDGF (platelet derived growth factor) produced by platelet Kupffer cells and the like, or activated by oxidation stress, it expresses α-smooth muscle actin (αSMA) and acquires smooth muscle cell property, whereby transforming into a myofibroblast-like cell. In addition, activated HSC exhibits an excessive expression of TGFβ receptor and the production of the extracellular matrix protein is promoted by an autocrine mechanism. The TGFβ also has a hepatocyte proliferation inhibiting effect.
Accordingly, we considered that if the action of the TGFβ and PDGF on the HSC could be suppressed by any method, it might lead to suppression of the hepatic fibrosis and serve to normalize the liver regeneration after hepatic disorder.
An objective of the invention is to provide a medicament which suppresses the hepatic fibrosis, promotes the liver regeneration and normalizes the liver.
Adiponectin is an animal adipose tissue-specific protein separated newly from human adipose tissue by Maeda et al in 1996, and its amino acid sequence is also known (Maeda K, et al. Biochem. Biophys. Res. Commun. 221: 286 (1996)).
Almost at the same time, other researchers identified a substance named ACRP30 cloned from mouse 3T3-F 442A cells (Scherer P E et al., J. Biol. Chem. 270: 26746–26749 (1995)), which is believed to be identical to adiponectin.
This adiponectin is abundantly present not only in an adipose tissue but also in blood. In normal human blood it is present at a level as high as 5 to 10 μg/ml (Arita Y et al., Biochem. Biophys. Res. Commun. 257: 79–83 (1999)).
Paradoxically, the blood level of this adiponectin is reduced as obesity advance.
The effect of the adiponectin was not elucidated entirely, although some researchers reported that it had a vascular smooth muscle proliferation on suppressing effect, a cell migration suppressing effect, an anti-arteriosclerotic effect, a suppressive effect on the activation of monocyte and macrophage, an anti-inflammatory effect and the like.